Insulin signaling at target tissues is essential for normal growth and development and for normal homeostasis of glucose, fat and protein metabolism. Control over this signaling therefore is tightly regulated and can be achieved by autoregulation, whereby downstream components inhibit upstream elements (homologous feedback) or through heterologous desensitization whereas signals from apparently unrelated pathways can inhibit insulin signaling thus leading to insulin resistance. Phosphorylation of IRS proteins on Ser residues has emerged as a key step in these feed-back control processes both under physiological and pathological conditions. Here we review a range of conditions that activate IRS kinases to phosphorylate IRS proteins on three 'hot-spot' domains and discuss their implications on insulin signaling, insulin resistance and Type-2 diabetes, an emerging epidemic of the 21^st century. The list of IRS kinases implicated in the development of insulin resistance is growing rapidly, concomitant with the list of potential Ser/Thr phosphorylation sites in IRS proteins. The flexibility versus specificity features of this phosphorylation are discussed and an array phosphorylation phenomenon rather then an event confined to few selected Ser sites will be suggested.